WO2008016700A2 - Composés de n-oxyde et utilisations thérapeutiques - Google Patents

Composés de n-oxyde et utilisations thérapeutiques Download PDF

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Publication number
WO2008016700A2
WO2008016700A2 PCT/US2007/017300 US2007017300W WO2008016700A2 WO 2008016700 A2 WO2008016700 A2 WO 2008016700A2 US 2007017300 W US2007017300 W US 2007017300W WO 2008016700 A2 WO2008016700 A2 WO 2008016700A2
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alkyl
compound
cancer
disorder
formula
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PCT/US2007/017300
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English (en)
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WO2008016700A3 (fr
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Alfred M. Ajami
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Xanthus Pharmaceuticals, Inc.
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Publication of WO2008016700A2 publication Critical patent/WO2008016700A2/fr
Publication of WO2008016700A3 publication Critical patent/WO2008016700A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to a class of novel compounds that can be used for treatment of an inflammatory disorder, a demyelinating disorder, a FLT3 -mediated disorder, a cancer, a leukemia or a CSF-I R-mediated disorder in a patient.
  • the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R is R x , or R and R 4 or, alternatively, R and R 5 taken together with their intervening carbon atoms form a 5, 6 or 7 member, optionally substituted, cycloalkyl or non-aromatic optionally substitued heterocycle containing one or two oxygens and optionally substituted with methyl or hydroxy 1.
  • R is a hydrolysable group.
  • R, alone or taken together with R 4 , or alternatively R 5 , and their intervening carbon atoms is a phenol isosteric group. The remainder of the variables in formula (I) take the following values:
  • R x is -H, an optionally substituted alkyl, hydroxyl, alkoxy group, or a halogen
  • R 2 is -H 3 an optionally substituted Cl-ClO alkyl or an optionally substituted aryl, an optionally substituted aralkyl or an optionally substituted heteroaryl;
  • R 3 is a group represented by a structural formula
  • n is an integer from 1 to 5;
  • R a and R b each independently are hydrogen or an optionally substituted alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a non- aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, provided that the heterocycle comprises no more than one ring nitrogen atom;
  • R 4 , R 5 and R 6 are each independently -H, -OH, a halogen or an optionally substituted C1-C6 alkoxy; or R 5 and R 6 taken together with their intervening carbon atoms, form a 5, 6 or 7 member, optionally substitited cycloalkyl or non-aromatic heterocycle.
  • the present invention is a method of treating a patient suffering from a demyelinating disorder, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a method of treating a patient suffering from an inflammatory disorder, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition, comprising a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
  • the present invention is the use a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a medicament useful for treating a patient suffering from a cancer.
  • the present invention is the use a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a medicament useful for treating a patient suffering from a demyelinating disorder.
  • the present invention is the use a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a medicament useful for treating a patient suffering from an inflammatory disorder.
  • the present invention is a compound of formula (I) below or a pharmaceutically acceptable salt thereof.
  • the present invention is a method of treating certain types of cancer, or an inflammatory disorder, or a demyelinating disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • R is either R x or taken together with R 4 or, alternatively, R 5 and their intervening carbon atoms form a 5, 6 or 7 member, optionally substituted, cycloalkyl or non-aromatic heterocycle containing one or two oxygens and optionally substituted with methyl or hydroxyl.
  • R is R x , wherein R x is -H, an optionally substituted alkyl, hydroxyl, alkoxy group, a halogen. More preferably, R x is -F, -OH or -OCH 3 .
  • R is a hydrolysable group.
  • R is selected from groups (II) - (VII):
  • R alone or taken together with R 4 , or alternatively R 5 , and their intervening carbon atoitns is a phenol isosteric group.
  • the phenol isosteric group is selected from:
  • R is -H, an optionally substituted Cl-ClO alkyl or an optionally substituted aryl, an optionally substituted aralkyl, or an optionally substituted heteroaryl.
  • R 2 is -H or an optionally substituted Cl-ClO alkyl. More preferably, R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl. Even more preferably, R 2 is a -H or a C1-C4 alkyl. Yet more preferably, R 2 is -H , methyl or ethyl.
  • R a and R b each independently are hydrogen or an optionally substituted alkyl, or R a and R , taken together with the nitrogen to which they are attached, form a non- aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, provided that the heterocycle comprises no more than one ring nitrogen atom.
  • R a and R b each independently are hydrogen or an alkyl, or R a and R , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy.
  • R a and R b is each independently a hydrogen or a C1-C3 alkyl, or, taken together with the nitrogen to which they are attached, form group R y selected form a group consisting of
  • R a and R b taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring.
  • R B and R b are independently each a -H or an alkyl optionally substituted with a C1-C4 hydroxyalkyl.
  • R a and R b are each independently a C1-C3 alkyl.
  • R a and R b are identical and are methyl or ethyl.
  • R 4 , R 5 and R 6 are each independently -H, -OH, a halogen or an optionally substituted C1-C6 alkoxy, or R 5 and R 6 taken together with their intervening carbon atoms, form a 5, 6 or 7 member, optionally substitited cycloalkyl or non-aromatic heterocycle.
  • R 4 , R 5 and R 6 are each independently -H, -OH, CI-C4 alkyl or C1-C4 haloalkyl, or R 5 and R 6 taken together are methylenedioxy.
  • R 4 is -H
  • R 5 and R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or taken together are methylenedioxy.
  • n is an integer from 1 to 5.
  • R 7 and R 8 are independently each H, optionally substituted C1-C6 alkyl, optionally substituted aryl or optionally substituted aralkyl.
  • R 7 and R 8 are independently each H, optionally substituted C1-C6 alkyl or phenyl or benzyl, each optionally substituted with one or more hydroxyl, C1-C3 alkoxy, amino, alkylamino, halogen, haloalkyl or haloalkoxy groups. More preferably, R 7 and R 8 are each independently H, methyl or ethyl.
  • R 9 is carboxyl, carboxamide optionally N-substituted or N, N '-di substituted with C1-C4 alkyl, C1-C6 alkanoyl, C1-C6 carbalkoxy, or optionally substituted aroyl.
  • R 9 is carboxyl, carboxamide optionally N-substituted or N 5 N '-di substituted with a C1-C4 alkyl, C1-C4 alkanoyl, or C1-C4 carbalkoxy. More preferably, R 9 is a Cl-C4 alkanoyl.
  • R 10 is H, optionally substituted C1-C6 alkyl or optionally substituted aryl or optionally substituted aralkyl.
  • R 10 (formula (V) and, independently, in formula (VII)) is H or C1-C4 alkyl, phenyl, or benzyl, each optionally substituted with one or more hydroxyl, C1-C3 alkoxy, amino, alkylamino, halogen, haloalkyl or haloalkoxy groups. More preferably, each R 10 (formula (V), and, independently, formula (VII)) is independently an H, or C1-C4 alkyl.
  • R u and R 12 are independently each H, optionally substituted C1-C6 alkyl or, taken together with the atom to which they are attached, form an optionally substituted non-aromatic heterocycle.
  • R 11 and R 12 (formula (IV)) are independently each a H, methyl or ethyl or, taken together with the nitrogen atom to which they are attached form non-aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, and optionally substituted at any one or more ring nitrogen atoms with C1-C4 alkyl or C1-C4 alkyl substituted with -NR c R d , wherein R c and R d are individually H, methyl or ethyl.
  • NR 11 R 12 is N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl or N-piperazinyl, optionally N'-substituted or N',N'-disubstituted with Cl -C4 alkyl or Cl -C4 alkyl substituted with -NR c R d , wherein R c and R d are individually H, methyl or ethyl.
  • R 13 and R 14 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkanoyl, or optionally substituted aroyl, or, taken together with the atom to which they are attached, form an optionally substituted heteroaryl or non-aromatic optionally substituted heterocycle.
  • R 16 is optionally substituted C1-C6 alkyl, optionally substituted aryl or aralkyl, C1-C6 alkanoyl, or optionally substituted aroyl.
  • R 16 (formula (V)) is a Cl - C6 alkanoyl, optionally substituted with -OH, -SH, halogen, cyano, nitro, amino, -COOH, a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl, or -(CH 2 ) q -C(O)OH, wherein q is an integer from 1 to 6. More preferably, R 16 (formula (V)) is a branched C3-C6 alkanoyl.
  • R 17 is H, C1-C6 alkyl, C1-C6 alkoxyalkyl, optionally substituted aryl or aralkyl or heteroaryl, optionally substituted aryloxy, aralkyloxy or heteroaryloxy, Q is O or S, and Z is CH or N .
  • R 17 is H, optionally substituted C 1 -C6 alkyl, or C 1 -C6 alkoxyalkyl, or.
  • phenyl, benzyl, phenyloxy or benzyloxy each optionally substituted with halogen, -NO 2 , -NH 2 , -COOH, C1-C3 alkyl, C1-C3 carbalkoxy, C1-C3 a alkoxy group, CI-C3 haloalkyl or C1-C3 haloalkoxy.
  • R 17 is H, C1-C4 alkyl, or phenyl, each optionally substituted with one or more halogen atoms, -NO 2 , -NH 2 , -COOH, C 1 -C3 alkyl, C 1 -C3 carbalkoxy, C 1 -C3 a alkoxy group, C 1 -C3 haloalkyl or C1-C3 haloalkoxy.
  • R 17 is H, C1-C4 haloalkyl or phenyl, each optionally substituted with one or more halogen atoms or C1-C3 haloalkyls.
  • R 17 is H, trifluoromethyl or phenyl substituted with one or more trifiuoromethyls.
  • R 21 is optionally substituted Cl-ClO alkyl, or an optionally substituted aryl or aralkyl or, R 21 and R 22 taken together with their intervening atoms form a 5-7 membered non-aromatic heterocycle.
  • R 21 is optionally substituted Cl-ClO alkyl, phenyl, or benzyl, each optionally substituted with a halogen, -NO 2 , -NH 2 , -COOH, alkyl, C1-C3 carbalkoxy, C1-C3 alkoxy group, C1-C3 haloalkyl or Cl- C3 haloalkoxy, or R 21 and R 22 , taken together with their intervening atoms, form a 5 or 6 membered non-aromatic heterocycle.
  • R 22 and R 23 are each independently -H, or a optionally substituted C1-C6 alkyl, provided that R 22 and R 23 are not simultaneously hydrogens.
  • R 22 and R 23 are each independently -H, or a C1-C3 alkyl.
  • R 100 is optionally substituted C1-C6 alkyl or optionally substituted aryl or optionally substituted aralkyl.
  • R 100 (formula (III)) is a C1-C4 alkyl.
  • R 101 is H, optionally substituted C1-C6 alkyl or optionally substituted aryl or optionally substituted aralkyl.
  • R 101 is H or C1-C4 alkyl. More preferably, R 101 (formula (VI)) is H, methyl or ethyl.
  • R 107 is optionally substituted C1-C6 alkyl, optionally substituted aryl or aralkyl, or a non-aromatic heterocycle, optionally substituted at one or more substitutable carbon atoms with methyl, hydroxyl, or methoxy, and optionally N'-substituted at any substitutable nitrogen atom with C1-C4 alkyl or C1-C4 alkyl substituted with -NR c R d .
  • R 107 is C1-C6 alkyl optionally substituted with -OH, -SH, halogen, cyano, nitro, amino, -COOH, a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl, or -(CH 2 VC(O)OH. More preferably, R 107 (formula (IX)) is C1-C6 alkyl or C1-C6 carboxyalkyl.
  • Q 1 is O or NH.
  • the group of formula (VI) is represented by structural formulas (Via) or (VIb):
  • Y is a halogen, -NO 2 , -NH 2 , -COOH, alkyl, C1-C3 carbalkoxy, C1-C3 alkoxy group, C1-C3 haloalkyl or C1-C3 haloalkoxy.
  • Ring A is a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, oxy, or methoxy, and optionally substituted at any one or more ring nitrogen atoms with C1-C4 alkyl or C1-C4 alkyl substituted with -NR c R d , wherein R c and R d are individually H, methyl or ethyl.
  • ring A in formula (VIb) is selected from:
  • R is a hydrolyzable group selected from groups (II) - (VII); and R 3 is
  • n is an integer from 1 to 5
  • R a and R b each independently are hydrogen or an alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy.
  • Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is a hydrolyzable group selected from groups (II) - (VII); R 3 is
  • n is an integer from 1 to 5
  • R a and R b each independently are hydrogen or an alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy;
  • R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl
  • R 4 , R 5 and R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R 5 and R 6 taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is a hydrolyzable group selected from groups (II) - (VII);
  • R 3 is wherein either n is 2 or 3 and R a and R b , is each independently a hydrogen or a C1-C3 alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form group R y selected form a group consisting of.
  • Q 2 is CH 2 , S or O
  • R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl
  • R 4 , R 5 arid R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R 5 and R 6 taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is a hydrolyzable group selected from groups (II) - (VII);
  • n is 2 or 3 and R a and R >b , is each independently a hydrogen or a C1-C3 aallkkyyll,, oorr RR aa a anndd RR bb ,, ttaakkeenn ttooggeetthheerr wwiitthh tthhee nniitrogen to which they are attached, form group R y selected form a group consisting of
  • Q 2 is CH 2 , S or O
  • R is a phenol isosteric group is selected from groups (X) - (XXIII):
  • n is an integer from 1 to 5
  • R a and R b each independently are hydrogen or an alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy.
  • Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is a phenol isosteric group is selected from groups (X) - (XXIII); R 3 is
  • n is an integer from 1 to 5
  • R a and R b each independently are hydrogen or an alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy;
  • R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl
  • R 4 , R 5 and R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R 5 and R 6 taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is a phenol isosteric group is selected from groups (X) - (XXIII);
  • n 2 or 3 and R a and R b , is each independently a hydrogen or a C1-C3 alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form group R y selected form a group consisting of
  • Q 2 is CH 2 , S or O
  • R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl
  • R 4 , R 5 and R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R 5 and R taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is a phenol isosteric group is selected from groups (X) - (XXIII);
  • n 2 or 3 and R a and R b , is each independently a hydrogen or a C1-C3 alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form group R y selected form a group consisting of
  • Q 2 is CH 2 , S or O
  • R is R x as defined above for formula (I);
  • n is an integer from 1 to 5
  • R a and R b each independently are hydrogen or an alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy.
  • Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is R";
  • n is an integer from 1 to 5
  • R a and R b each independently are hydrogen or an alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy
  • R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl
  • R 4 , R 5 and R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R 5 and R 6 taken together are methylenedioxy.
  • Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is R x ;
  • n 2 or 3 and R a and R b , is each independently a hydrogen or a C1-C3 alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form group R y selected form a group consisting of
  • Q 2 is CH 2 , S or O
  • R 2 is -H, C1-C4 alkyl or C1-C4 haloalkyl
  • R 4 , R 5 and R 6 are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R 5 and R 6 taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).
  • R is R x ;
  • n 2 or 3 and R a and R b , is each independently a hydrogen or a C1-C3 alkyl, or R a and R b , taken together with the nitrogen to which they are attached, form group R y selected form a group consisting of
  • Q 2 is CH 2 , S or O
  • Values and preferred values for the remainder of the variables are as described for formula (I).
  • the compound of formula (I) is represented by structural formula (XXX):
  • R is -F, -OH or -OCH 3 , n is 2 or 3, and values and preferred values for R 2 , R a and R b are as defined for formula (I). Even more preferably, R is -F, -OH or -OCH 3 , n is 2 or 3, and R 2 is a -H or a C1-C4 alkyl. Values and preferred values for R a and R b are as defined for formula (I).
  • R is -F, -OH or -OCH 3 , n is 2 or 3, and R 2 is a -H or a Cl- C4 alkyl, and R a and R b are each independently a C1-C3 alkyl.
  • R is -F, -OH or -OCH 3 , n is 2 or 3
  • R 2 is a -H or a Cl -C4 alkyl
  • R a and R b are independently each a -H or an alkyl optionally substituted with a C1-C4 hydroxyalkyl.
  • R is -F, -OH or -OCH 3
  • R a and R b are identical and are methyl or ethyl, or taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring
  • n is 2 or 3
  • R 2 is a hydrogen or a C1-C4 alkyl.
  • n is 2 or 3.
  • the remainder of the variables take the values and preferred values defined above in formula (I).
  • R 2 is a -H or a Cl- C4 alkyl.
  • the remainder of the variables take the values and preferred values defined above in formula (I).
  • R a and R b are each independently a C1-C3 alkyl.
  • the remainder of the variables take the values and preferred values defined above in formula (I).
  • R a and R b are independently each a -H or an alkyl optionally substituted with a C1-C4 hydroxyalkyl.
  • the remainder of the variables take the values and preferred values defined above in formula (I).
  • R is -F, -OH or -OCH3
  • R a and R b are identical and are methyl or ethyl, or taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring
  • n is 2 or 3
  • R 2 is a hydrogen or a C1-C4 alkyl.
  • Examples of compounds of formula (I) include:
  • alkyl includes straight or branched saturated monovalent hydrocarbon radicals, typically Cl-ClO, preferably Cl- C6.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
  • Suitable substituents for a substituted alkyl include -OH, -SH, halogen, cyano, nitro, amino, -COOH, a C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl.
  • cycloalkyl is a non-aromatic saturated carbocyclic moieties, typically C3-C8.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Suitable substituents for a cycloalkyl are defined above for an alkyl.
  • haloalkyl includes an alkyl substituted with one or more F, Cl, Br, or I, wherein alkyl is defined above.
  • alkoxy means an “alkyl-O-" group, wherein alkyl, is defined above.
  • alkanoyl as used herein, means an “alkyl-C(O)-" group, wherein alkyl is defined above.
  • haloalkoxy means “haloalkyl-O-", wherein haloalkyl is defined above.
  • aryl refers to a carbocyclic aromatic group.
  • aryl groups include, but are not limited to phenyl and naphthyl.
  • heteroaryl refers to aromatic groups containing one or more heteroatoms (O, S, or N).
  • a heteroaryl group can be monocyclic or polycyclic, e.g. a monocyclic heteroaryl ring fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups.
  • the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofiiranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophen
  • non-aromatic heterocycle refers to non-aromatic carbocyclic ring systems typically having four to eight members, preferably five to six, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S.
  • Non aromatic heteroccyles can be optionally unsaturated.
  • non- aromatic heterocyclic rings examples include 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl, [l,3]-dioxalanyl, [l,3]-dithiolanyl, [1,3]- dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3- mo ⁇ holinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrorolidinyl, 1-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N- substituted diazolonyl, and 1-pthalimi
  • heteroaryl or non-aromatic heterocyclic groups may be C-attached or N- attached (where such is possible).
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • Suitable substituents for an aryl, a heteroaryl, or a non-aromatic heterocyclic group are those that do not substantially interfere with the pharmaceutical activity of the disclosed compound.
  • One or more substituents can be present, which can be identical or different.
  • suitable substituents for a substitutable carbon atom in aryl, heteroaryl or a non-aromatic heterocyclic group include -OH, halogen (-F, -Cl, -Br, and -I), -R', haloalkyl, -OR', -CH 2 R', -CH 2 OR', -CH 2 CH 2 OR', -CH 2 OC(O)R', -O-COR', -COR', -SR', -SCH 2 R', - CH 2 SR', -SOR', -SO 2 R', -CN, -NO 2 , -COOH, -SO 3 H, -NH 2 , -N
  • R" is hydrogen, an alkyl or alkoxy group.
  • the "activated alkanoic acylating agent" is defined within the references cited.
  • This acetimidate reacts with the amine in compound (S 1.3) and cyclized to the methyl or ethyl or other alkylimidazole, again per the cited articles.
  • compounds of formula (I) can be used to treat an inflammatory disorder, a demyelinating disorder, a FLT3 -mediated disorder, a cancer, a leukemia or a CSF-lR-mediated disorder in a patient.
  • patient means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
  • treat or “treating” include any treatment, including, but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or preventing or slowing the appearance of symptoms and progression of the named disorder or condition.
  • the present invention is a method of treating a patient suffering from a cancer.
  • the method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a method of treating a subject suffering from a cancer.
  • cancer refers to the uncontrolled growth of abnormal cells that have mutated from normal tissues.
  • a cancerous tumor (malignancy) is of potentially unlimited growth and expands locally by invasion and systemically by metastasis.
  • cancers examples include: breast cancer, colorectal cancer, non-small cell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck, hepatocellular, thyroid, multidrug-resistant leukemia, lymphoma, multiple myeloma, esophageal, large bowel, pancreatic, mesothelioma, carcinoma (e.g. adenocarcinoma, including esophageal adenocarcinoma), sarcoma (e.g.
  • the patient can be treated for bone metastases. Treatment of subtypes of the aforementioned cancers is also included. Subtypes are described in the following paragraphs.
  • Treating a subject suffering from cancer includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components).
  • Treating a bone metastases refers to reducing (partially or completely) the size of the bone metastases, slowing the growth of the metastases relative to the absence of treatment and reducing the extent of further spread of the cancer. "Treating a bone metastases” also includes pain reduction, decreased incidents of fractures, relief of spinal cord compression, control of hypercalcaemia, and/or restoration of normal blood cell counts.
  • Breast cancer includes, but is not limited to, ductal carcinoma, lobular carcinoma, inflammatory carcinoma, medullary carcinoma, colloid or mucinous carcinoma, papillary carcinoma, tubular carinoma, triple negative breast cancer, inflammatory breast cancer, metaplastic carcinoma, Paget's disease, and Phyllodes tumor.
  • ovarian cancer is cancer of the ovaries or fallopian tubes, including cancers of germ cells, stromal cells, and epithelial cells.
  • ovarian cancers include but are not limited to:
  • Epithelial Ovarian Tumors which include but are not limited to, serous adenomas, mucinous adenomas, and Brenner tumors, tumors of low malignant potential (LMP tumors), borderline epithelial ovarian cancer, epithelial ovarian cancers, carcinomas and undifferentiated epithelial ovarian carcinomas;
  • Germ Cell tumors which include but are not limited to, teratoma, dysgerminoma, endodermal sinus tumor, and choriocarcinoma; and
  • Stromal tumors which include but are not limited to, granulosa cell tumors, granulosa-theca tumors, and Sertoli-Leydig cell tumors.
  • Renal cancer or “kidney cancer”, as used herein, includes but is not limited to, transitional cell cancer (TCC) of the renal pelvis, Wilms Tumour and renal cell cancer. Renal cell cancer is also called renal adenocarcinoma or hypernephroma. In renal cell cancer, the cancerous cells are found in the lining of the tubules (the smallest tubes inside the nephrons that help filter the blood and make urine).
  • TCC transitional cell cancer
  • Renal cell cancer is also called renal adenocarcinoma or hypernephroma.
  • the cancerous cells are found in the lining of the tubules (the smallest tubes inside the nephrons that help filter the blood and make urine).
  • renal cell cancer There are several types of renal cell cancer including but not limited to clear cell, chromophilic, chromophobe, oncocytic, collecting duct and sarcomatoid.
  • Renal cancer also includes cancers containing more than one of the cell types described above.
  • melanoma is a type of skin cancer that occurs in the cells that color the skin, called melanocytes.
  • Types of melanoma include but are not limited to: Cutaneous melanoma, superficially spreading melanoma, nodular malignant melanoma, lentiginous malignant melanoma, acral lentiginous melanoma, demoplastic malignant melanomas, giant melanocyte nevus, amelanotic malignant melanoma, acral lentiginous melanoma unusual melanoma variants, including mucosal malignant melanoma and ocular malignant melanoma.
  • Sphercomas include but are not limited to, fibrosarcomas from fibrous body tissues, leiomyosarcomas and rhabdomyosarcomas from muscle tissues, liposarcomas from fat, synovial sarcomas, angiosarcomas from blood vessels, MPNST - malignant peripheral nerve sheath tumours (PNSTs), GIST - gastrointestinal stromal sarcoma, osteosarcoma, myosarcoma, chondrosarcoma, bile duct sarcoma, brain sarcoma, breast sarcoma, soft tissue sarcoma, uterine sarcoma, endocardial sarcoma, stromal sarcomas from supporting tissues (endometrial stromal sarcoma), granuloytic, histiolytic, hemangioendothelial, Kupffer-cell, neurogenic, round-
  • the sarcoma is leiomyosarcoma or liposarcoma.
  • thyroid cancer includes but is not limited to, papillary and/or mixed papillary/follicular, follicular and/or Hurthle cell, lymphoma, medullary, anaplastic and combinations thereof.
  • head and neck cancer encompasses tumors that occur in several areas of the head and neck region, including the nasal passages, sinuses, mouth, throat, larynx (voice box), swallowing passages, salivary glands, and skin cancers that develop on the scalp, face, or neck may also be considered head and neck cancers.
  • cancers include but are not limited to squamous cell carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, lymphoma, adenocarcinoma, esthesioneuroblastoma, tumors of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, cancers of the oral cavity (including all the various parts of the mouth: the lips; the lining inside the lips and cheeks (the buccal mucosa); the bottom of the mouth; the front of the tongue; the front part of the top of the mouth (the hard palate); the gums; and the area behind the wisdom teeth (the retromolar trigone)), tumors of the oropharynx, hypopharyngeal tumors, laryngeal cancer and salivary gland cancer (including malignant salivary gland tumor).
  • hepatocellular cancer or “liver cancer” includes but is not limited to: hepatocellular carcinoma (also sometimes called hepatoma or HCC) "carcinoma", fibrolamellar HCC, cholangiocarcinoma, angiosarcoma (also be called haemangio sarcoma) and hepatoblastoma.
  • non-small cell lung cancer includes, squamous cell carcinoma, adenocarcinoma and undifferentiated non-small cell lung cancer (undeveloped cancer cells are known as undifferentiated cells) and large cell carcinoma.
  • Colorectal cancer includes any type of colon or rectal cancer, including but not limited to, adenoscarcinoma, sarcoma, melanoma, stromal, carcinoid, and lymphoma.
  • the present invention is a method of treating a patient suffering from an inflammatory condition.
  • the method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the condition can be systemic lupus, inflammatory bowl disease, psoriasis, Crohn's disease, rheumatoid arthritis, sarcoid, Alzheimer's disease, insulin dependent diabetes mellitus, atherosclerosis, asthma, spinal cord injury, stroke, a chronic inflammatory demyelinating neuropathy, multiple sclerosis, a congenital metabolic disorder, a neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, a hereditary demyelinating condition, a prion-induced demyelination, encephalitis-induced demyelination.
  • Examples of chronic inflammatory demyelinating neuropathies include:
  • CIDP Chronic Immune Demyelinating Polyneuropathy
  • multifocal CIDP multifocal motor neuropathy
  • anti-MAG Syndrome Neuropathy with IgM binding to Myelin-Associated Glycoprotein
  • GALOP Syndrome Gait disorder Autoantibody Late-age Onset Polyneuropathy
  • anti-sulfatide antibody syndrome anti-GM2 gangliosides antibody syndrome
  • POEMS syndrome Polyneuropathy Organomegaly Endocrinopathy or Edema M-protein Skin changes
  • perineuritis and IgM anti-GDlb ganglioside antibody syndrome.
  • the present invention is a method of treatment of a patient suffering from a demyelinating condition.
  • the method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • a "demyelinating condition” is a condition that destroys, breaks the integrity of or damages a myelin sheath.
  • myelin sheath refers to an insulating layer surrounding vertebrate peripheral neurons, that increases the speed of conduction and formed by Schwann cells in the peripheral or by oligodendrocytes in the central nervous system.
  • Such condition can be multiple sclerosis, a congenital metabolic disorder, a neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, a hereditary demyelination condition, a prion-induced demyelination, encephalitis-induced demyelination, a spinal cord injury, Alzheimer's disease as well as chronic inflammatory demyelinating neuropathies, examples of which are given above.
  • the condition is multiple sclerosis.
  • the method comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a method of promoting remyelination of nerve cells in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I).
  • the patient can be suffering from any of the demyelinating conditions listed above.
  • the present invention is a method of preventing demyelination and promoting remyelination in a patient in need thereof, comprising administering a combination of a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof, and an anti-inflammatory agent as described below.
  • the present invention is a method of reversing paralysis in a subject in need thereof with a demyelinating disease, comprising administering to the subject a compound in an amount sufficient to inhibit lymphocyte infiltration of immune cells in the spinal cord to promote remyelination of nerve cells in the spinal cord and thereby treating paralysis in said subject, wherein the compound is of formula formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a method of treating a patient suffering from an acute myeloid leukemia characterized by a FLT3 mutation.
  • the method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the term "FLT3 -mediated disorder” is a disorder in which one or more symptoms can be inhibited, alleviated, reduced or whose onset can be delayed by inhibiting completely or partially the FLT3 protein kinase.
  • the terms "treat” or “treating”, when used with reference to a FLT3 -mediated condition, include any treatment, including, but not limited to, alleviating symptoms, eliminating the causation of the symptoms associated with a FLT3-mediated condition either on a temporary or permanent basis, or preventing or slowing the appearance of symptoms and progression of the named disorder or condition.
  • the term "therapeutically effective amount”, when used with reference to a FLT3-mediated condition, is the amount of a compound disclosed herein that will achieve a partial or total inhibition or delay of the progression of a FLT3- mediated disorder in a patient.
  • FLT3-mediated disorders and conditions include axonal degeneration, acute transverse myelitis, amyotrophic lateral sclerosis, infantile spinal muscular atrophy, juvenile spinal muscular atrophy, Creutzfeldt- Jakob disease, subacute sclerosing panencephalitis, organ rejection, bone marrow transplant rejection, non-myeloablative bone marrow transplant rejection, ankylosing spondylitis, aplastic anemia, Behcet's disease, graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia,
  • FLT3 Fms-like tyrosine kinase; other names include CDl 35, FLK2 (Fetal liver kinase 2), STKl (Stem cell kinase I)) is a class III receptor tyrosine kinase (RTK) structurally related to the receptors for platelet derived growth factor (PDGF), colony stimulating factor 1 (CSFl), and KIT ligand (KL).
  • RTKs contain five immunoglobulin-like domains in the extracellular region and an intracellular tyrosine kinase domain split in two by a specific hydrophilic insertion (kinase insert).
  • FLT3 closely related to PDGF receptors and c-Kit is, however, not inhibited by the small molecule inhibitors of PDGF and c-Kit; (G Del Zotto et al., J. Biol. Regulators Homeostatic Agents 15: 103-106, 2001).
  • the compounds of the present invention can be used to treat certain leukemias, including FLT3- mediated leukemias.
  • Leukemias are selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL).
  • HCL hairy cell leukemia
  • leukemia is a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms.
  • Acute lymphocytic leukemia also known as Acute Lymphoblastic Leukemia, or ALL
  • ALL Acute Lymphoblastic Leukemia
  • Acute myelogenous leukemia also known as Acute Myeloid Leukemia, or AML
  • AML Acute Myeloid Leukemia
  • This type of leukemia was previously called acute nonlymphocytic leukemia.
  • Chronic lymphocytic leukemia (CLL) most often affects adults over the age of
  • CML chronic myelogenous leukemia
  • HCL leukemia is an incurable, indolent blood disorder in which mutated, partly matured B cells accumulate in the bone marrow. Its name is derived from the shape of the cells, which look like they are covered with short, fine, hair-shaped projections. Unlike any other leukemia, HCL is characterized by low white blood cell counts.
  • the present invention is a method of treating a CSF-IR- mediated condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Colony Stimulating Factor -1 Receptor (CSF-IR) signaling play an important role in the etiology of the disorders and conditions described above is well known and is described, for example in Simoncic et al, Mol.Cel. Biol., Vol. 26, No. 11 (2006), pp. 41-49-4160.; Yang et al., Ann. Rheum. Dis. (2006); 65, pp. 1671-1672; Irving et al, The FASEB J., Vol.
  • CSF-lR-mediated disorders include cardiovascular disease (e.g. artherial sclerosis), diseases with an inflammatory component including glomerulonephritis, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain, osteoporosis, Paget's disease, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone, uterine cancer, stomach cancer, hairy cell leukemia, Sjogren's syndrom, or uveitis.
  • the disorders include cancers such as osteolytic sarcoma, myeloma, and tumor metastasis to bone, uterine cancer, stomach cancer, hairy cell
  • therapeutically effective amount means an amount of the compound, which is effective in treating the named disorder or condition. In certain embodiments, therapeutically effective amount means an amount sufficient to effect remyelination of nerve cells in a patient.
  • compounds of formula (I) can be administered in any form or mode which makes the compound bioavailable in therapeutically effective amounts.
  • compounds of formula (I) can be administered in a form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the present invention.
  • “Pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (I).
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p- toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2- hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form.
  • “Pharmaceutically acceptable basic addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of formula (I). Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline.
  • alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides
  • ammonia and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline.
  • the selection of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
  • Compounds of the present invention can be administered by a number of routes including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermal Iy, intranasally, rectally, topically, and the like.
  • routes including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermal Iy, intranasally, rectally, topically, and the like.
  • routes including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermal Iy, intranasally, rectally, topically, and the like.
  • routes including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermal Iy, intranasally, rectally, topically, and the like.
  • compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.
  • Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials.
  • the compound of formula (I) of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsif ⁇ ers and stabilizers.
  • the dosage range at which the disclosed compounds, for example, compounds of formula (I), including the above-mentioned examples thereof, exhibit their ability to act therapeutically can vary depending upon the severity of the condition, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient.
  • the compounds described herein will exhibit their therapeutic activities at dosages of between about 0.1 mg/m 2 free base equivalent per square meter of body surface area/single dose to about 1000 mg/m 2 free base equivalent per square meter of body surface area/single dose.
  • These dosages can be administered, for exaple, once per week, once every other week, once every third week or once per week for three out of every four weeks.
  • the disclosed compounds can be administered daily (typically orally).
  • Daily dose of administration of the compounds of the present invention can be repeated, in one embodiment, for one week.
  • daily dose can be repeated for one month to six months; for six months to one year; for one year to five years; and for five years to ten years.
  • Representative total daily doses would include those in the range of 10-2000 mg.
  • the total daily dose can be divided into equal doses and administered twice daily, thrice daily, or four times daily.
  • the length of the treatment by repeated administration is determined by a physician.
  • the dosage range at which the disclosed compounds of formula (I) exhibit their ability to act therapeutically can vary depending upon the severity of the condition, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient.
  • the inventive compounds of the invention will exhibit their therapeutic activities at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.
  • the dosage can be 0.1-100 mg/kg per every other day or per week.
  • Combination Therapies The compounds used in the present invention can be administered alone or in combination with one or more other pharmaceutically active agents that are effective against the inflammatory condition and/or the demyelating disorder being treated.
  • the term “combination” with reference to pharmaceutically active agents and the term “co-administering” and “co-administration” refer to administering more than one pharmaceutically active agent to a patient during one treatment cycle and not necessarily simultaneous or in a mixture.
  • the compounds of the present invention are administered in combination with an anti-inflammatory agent.
  • the anti -inflammatory agent can be adrenocorticotropic hormone, a corticosteroid, an interferon, glatiramer acetate, or a non-steroidal anti-inflammatory drug (NSAID).
  • NSAID non-steroidal anti-inflammatory drug
  • Suitable anti-inflammatory agents include corticosteroid such as prednisone, methylprednisolone, dexamethasone Cortisol, cortisone, fludrocortisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, or betamethasone.
  • Suitable anti-inflammatory agents include NSAIDs such as aminoarylcarboxylic acid derivatives (e.g., Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid), arylacetic acid derivatives (e.g., Acematicin, Alclofenac, Amfenac, Bufexamac, Caprofen, Cinmetacin, Clopirac, Diclofenac, Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozic Acid, Fenoprofen, Fentiazac, Flubiprofen, Glucametacin, Ibufenac, Ibuprofen, Indomethacin, Isofezolac, Isoxepac, Ketoprofen, Lonazolac, Met
  • anti-inflammatory agents include aspirin, a sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine, a para-aminophenol derivatives, an indole, an indene acetic acid, a heteroaryl acetic acid, an anthranilic acid, an enolic acid, an alkanones, a diaryl- substituted furanone, a diaryl-substituted pyrajzoles, an indole acetic acids, or a sulfonanilide.
  • the compounds of the present invention can be administered in combination with immunotherapeutic agents such as interferons and anti-integrin blocking antibodies like natalizumab.
  • agents suitable for treating demyelinating disorders include Pirfenidone, Epalrestat, Nefazodone hydrochloride, Memantine hydrochloride, Mitoxantrone hydrochloride, Mitozantrone hydrochloride, Thalidomide, Roquinimex, Venlafaxine hydrochloride, Intaxel, Paclitaxel, recombinant human nerve growth factor; nerve growth factor, ibudilast, Cladribine, Beraprost sodium, Levacecarnine hydrochloride; Acetyl-L-carnitine hydrochloride; Levocamitine acetyl hydrochloride, Droxidopa, interferon alfa, natural interferon alpha, human lymphoblastoid interferon, interferon beta- Ib, interferon beta-Ser, Alemtuzumab, Mycophenolate mofetil, Zoledronic acid monohydrate, Adapalene, Eliprodil, Donepezil hydrochloride
  • the compounds of the present invention can be administered in combination with one or more other pharmaceutically active agents that are effective against multiple sclerosis.
  • agents include the interferons (interferon beta 1-a, beta 1-b, and alpha), glatiramer acetate or corticosteroids such as methylprednisolone and prednisone as well as chemotherapeutic agents such as mitoxantrone, methotrexate, azathioprine, cladribine cyclophosphamide, cyclosporine and tysabri.
  • T-cell receptor (TCR) V ⁇ 6 CDR2 peptide vaccine consisting of TCR V ⁇ 6, amino acid sequence 39-58, Leu - GIy - GIn - GIy - Pro - GIu - Phe - Leu - Thr - Tyr - Phe - GIn - Asn - GIu - Ala - GIn - Leu - GIu - Lys - Ser (SEQ ID NO:1);
  • Myelin basic protein immunogen peptide aminoacid sequence 75-95, Lys - Ser - His - GIy - Arg - Thr - GIn - Asp - GIu - Asn - Pro - VaI - VaI - His - Phe - Phe - Lys - Asn - He - VaI - Thr (SEQ ID NO:2);
  • Tiplimotide myelin basic protein immunogen vaccine peptide, aminoacid sequence 83-99, D - Ala - lys - pro - val - val - his - leu - phe - ala - asp - ile - val - thr - pro - arg - thr - pro, (SEQ ID NO:3);
  • Myelin basic protein immunogen peptide aminoacid sequence 82-98, Asp - glu - asp - pro - val - val - his - phe - phe - lys - asp - ile - val - thr - pro - arg - thr, (SEQ ID NO:4);
  • Adrenocorticotropic hormone Ser - Tyr - Ser - met - glu - his - phe - arg - try - gly - lys - pro - val - gly - lys- lys - arg - arg - pro - val - lys - val - tyr- pro - asp - gly - ala - glu - asp - glu - leu - ala - glu - ala - phe - pro - leu - glut - phe, (SEQ ID NO:5).
  • compositions of the present invention include compounds listed in FIG. 14. Additionally, Copaxone (Glatiramer) can be orally co-administered with the compounds of the present invention.
  • pharmaceutically active agents that are effective against multiple sclerosis and are suitable to be administered in combination with compounds of the present invention include compounds include: Mylinax, an oral formulation of cladrlbine used in leukaemia treatment, developed by Serono/Ivex; Teriflunomide, a metabolite of Arava, an oral immunosuppressant, developed by Sanofl-Aventis; FTY 720, an oral immunomodulator (Sphingosine-1 -phosphate receptor agonist), developed by Novartis; MBP 8298, a synthetic myelin basis protein designed to reduce the emergence of antibodies directed against the myelin, developed by Bio MS Medical; an orphan drug 4-aminopyridline (4-AP) 5 a potassium channel blocker, developed by Acorda; Gamunex, an intravenous immunoglobulin formulation, developed by Bayer; BG- 12 fumarate, a second generation oral futnarate, developed by Biogen Idec/Fumapharm; Temsiroli
  • compounds of formula (A) can be administered in combination with antivascular agents, in particular agents inhibiting the growth factor receptors, Epidermal Growth Factor Receptor (EGFR), Vascular Epidermal Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR).
  • antivascular agents in particular agents inhibiting the growth factor receptors, Epidermal Growth Factor Receptor (EGFR), Vascular Epidermal Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR).
  • agents include, Iressa, Tarceva, Erbitux, Pelitinib, AEE-788, CP-547632, CP- 547623, Tykerb (GW-2016), INCB-7839, ARRY-334543, BMS-599626, BIBW-2992, Falnidamol, AG1517, E-7080, KRN-951 , GFKI-258, BAY-579352, CP-7055, CEP- 5214, Sutent, Macugen, Nexavar, Neovastat, Vatalanib succinate, GW-78603413,
  • compounds of formula (I) can be administered in combination with agents that affect T-cell homing, extravastion and transmigration.
  • agents that affect T-cell homing, extravastion and transmigration include, FTY-720PKI-166, PTK-787, SU-11248.
  • compounds of formula (I) can be administered in combination with agents inhibiting VLA-4.
  • agents inhibiting VLA-4 include, Tysabri, Bio-1211. HMR-1031, SB-683698, RBx-4638,RO-0272441, RBx-7796,SB-683699, DW-908e, AJM-300, and PS-460644.
  • the compound of formula (I) can be administered alone or in combination with an anti -cancer agent.
  • the term “combination” with reference to pharmaceutically active agents and the term “co-administering” and “co-administration” refer to administering more than one pharmaceutically active agent to a patient during one treatment cycle and not necessarily simultaneous or in a mixture.
  • Anti-cancer agents that can be employed in combination with the compounds of the invention include TaxolTM (also referred to as “paclitaxel", and compounds that have the basic taxane skeleton), Adriamycin, Dactinomycin, Bleomycin, Vinblastine,
  • Cisplatin acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladrib
  • anti-cancer drugs that can be employed in combination with the compounds described herein include: 20-epi-l,25 dihydroxy vitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing mo ⁇ hogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara
  • BCR/ ABL antagonists benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicapro
  • UBC inhibitors are 5-fluorouracil and leucovorin.
  • chemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones.
  • alkylating agents include but are not limited to alkylating agents, antimetabolites, natural products, or hormones.
  • the invention is illustrated by the following examples, which are not intended to be limiting in any way.
  • Compound (XXXa) was prepared from the precursor imidazoacridinone as follows: a solution of m-chloroperbenzoic acid (1 18 mg, 0.685 mmol, 1.2eq) was dissolved in chloroform (5 ml), and added dropwise to a stirred solution of the precursor (200 mg, 0.571 mmol, leq) in a mixture of chloroform /methanol (5 ml / 1 ml) at 0-5 0 C. Stirring was continued 24h, during which time the mixture was allowed to equilibrate with room temperature.
  • Compound (XXXb) was prepared from the precursor imidazoacridinone as follows: a solution of m-chloroperbenzoic acid (110 mg, 0.637 mmol, 1.2eq) was dissolved in chloroform (5 ml) and added dropwise to a stirred solution of the precursor (200 mg, 0.548 mmol, leq) in chloroform (5 ml) at 0-5 0 C. Stirring was continued 24h, during which time the mixture was allowed to equilibrate with room temperature.
  • Compound (XXXc) was prepared from the precursor imidazoacridinone as follows: a solution of m-chloroperbenzoic acid (123 mg, 0.714 mmol, 1.2eq) was dissolved in chloroform (5 ml) and added dropwise to a stirred solution of the precursor (200 mg, 0.595 mmol, leq) in chloroform (5 ml) at 0-5 0 C. Stirring was continued 24h, during which time the mixture was allowed to equilibrate with room temperature.
  • EXAMPLE 2 Imidazoacridinone N-oxides are cytotoxic to cancer cells and the cytotoxicity increases under hypoxic conditions.
  • Three human leukemia cell lines were used to test the amine oxide compounds of this invention. They were chosen to be representative of cancer cells which may be grown under normoxic and also under hypoxic conditions, the latter to simulate the conditions prevailing in solid tumor cancers.
  • the three cell lines obtained from the American Type Culture Collection and grown as recommended, included the so called RS4(11) lymphoblastic translocation mutant, the so called myelomonocytic MV4(11) translocation mutant, and HL-60, an immortalized promyelocyte leukemia line that differentiates to either granulocytes or monocytes.
  • This latter leukemia cell may be considered also to serve as a model for the precursor cell lineage from which inflammatory cells are also derived
  • MTS cell proliferation assay CellTiter 96 Aqueous non-radioactive cell proliferation assay (Promega cat#G5421).
  • the resulting dose response curves were fitted to the four parameter Hill equation, a sigmoid saturation viability inhibition function, and the median lethality effect, or LC50 as the percent change in viability from control.
  • normoxic conditions the cells were grown in air containing 5% CO 2 .
  • hypoxic conditions the cells were grown for 24 hrs under normoxic conditions prior to test compound exposure and thereafter under nitrogen containing 2% O 2 and 5% CO 2 .
  • Cancer cells have been shown to undergo abnormal metabolism associated with the over production of metabolites triggered by reactive oxygen species and the concomitant increased titers of bioreducing factors, such as NADH and NADPH. Under these conditions, cancer cells are known to reduce tertiary amine N-oxides back to their parent alkylamines and thereby generate, in a manner selective to their own hypoxic conditions, a more active chemotherapeutic species. Bioreductive activation is a generally accepted phenomenon that accompanies the peculiar features of cancer cell biology and permits these cell types to be targeted selectively in the presence of normal cells. • .
  • EXAMPLE 3 Imidazoacridinone N-oxides Alleviate the Symptoms of Collagen Antibody Induced Arthritis in the Mouse, an Animal Model of Rheumatoid Arthritis and Autoimmune Disease
  • RA Rheumatoid Arthritis
  • RA is an autoimmune disorder characterized by the chronic erosive inflammation in joints leading to the destruction of cartilage and bones mediated by autoreactive inflammatory cells, such as macrophages.
  • One of the biochemical hallmarks of the disease, especially in connection macrophages, is the generation of hypervalent oxygen species similar to those which accumulate during periods of cellular hypoxia and free radical stress.
  • Overproduction of biological reductant species are also generated as part of the cellular erosive process in part to provide electronic mass balance to over production of oxygen radicals. It follows from these circumstance that an effective treatment might be targeted at the causative autoreactive cells by taking advantage of the bioreductive phenomenology as a means of pro-drug activation. Any agents that are not activated by bioreduction, as would be the case in normal tissues, should prove less intrinsically harmful.
  • DMARDS disease modifying antirheumatic drugs
  • TNF- ⁇ tumor necrosis factor ⁇
  • MTX methotrexate
  • CIA Collagen-induced Arthritis
  • rodents rat and mouse
  • nonhuman primates by immunization with type II collagen, the major constituent protein of articular cartilage.
  • CIA manifests as swelling and erythema in the limbs of the mouse.
  • This model of autoimmunity shares several clinical and pathological features with rheumatoid arthritis (RA) and has become the most widely studied model of RA.
  • CIA in the mouse model was first described by Courtenay et al. in 1980 (Courtnay, J.S., Dallman, M.J., Dayman, A.D., Martin A., and Mosedale, B.
  • CO (Cn) volume of day 0 (day n) in vehicle control
  • Imidazoacridinone N-oxides demonstrated anti-arthritic activity in the mouse CIA model, with significant anti-inflammatory activity on day 10 and day 14. These findings are relevant in the context of autoimmune disease in general because they exemplify the efficacy of the imidazoacridinone N-oxide compounds of this invention via an unexpected mechanism, e.g. bioreductive activation that targets macrophages and other autoreactive cells involved in the degenerative phases of disease.
  • the collagen antibody model of rheumatoid arthritis is significant because it by-passes the primary inflammatory insult of antigen presentation.
  • Classical anti -inflammatories like the corticosteroids and anti-folates like methotrexate alleviate the consequence of autoimmune inflammatory diseases by suppressing the primary events of inflammatory cell activation and recruitment.
  • the antibody induced model generates the symptoms of disease that present in the later stages of the autoimmune response, after activated cells become invasive into cartilage, having extravasated and transmigrated.
  • Methotrexate a benchmark therapeutic agent, has been shown to yield diminishing benefit in antibody induced models, which are intrinsically less dependent on T-cell activation than on their trafficking and migratory properties.
  • the work of Lange et al. can be cited in this context ⁇ Annals of Rheumatoid Disease 64:599-605, 2005).
  • the novel imidazoacridinone N-oxides described here appear fully active.
  • the results presented in this example are especially relevant to the treatment of human subjects, because the therapeutic effect was obtained by oral administration. In the era of injectable biologies, such as blocking antibodies, the addition of an effective, non-immunosuppressive therapy via the oral route is particularly desirable.
  • imidazoacridinone N-oxide genus emerges from the observation that they show marginal cytotoxicity until activated under conditions prevalent in tissues with hypoxic disease. This property can be expected to significantly lessen side effects, which otherwise would accrue from collateral damage to normal tissues.
  • Example 4 Efficacies of Representative Compounds of the Invention Efficacies a compound of formula (A)
  • IC50 IC50
  • EC50 EC50
  • DR dose respose
  • ElOOO percent inhibition at 1000 nMolar determined by assay. EC50 was calculated based on dose response curve was fitted to 4 parameter Hill equation.
  • the approach is based on treating each specific kinase with a unique substrate and optical reporter system in the presence of ATP at 100 micromolar.
  • the substrate is phosphorylated and a baseline optimal response is recorded.
  • Compounds were initially tested at 1000 nanomolar concentrations and the % inhibition of enzyme activity determined (ElOOO). The compounds were then re-tested by adding graded amounts of putative inhibitor which were added in 5 separate increments to generate a dose response curve. The latter is obtained by fitting to a 4 parameter Hill equation, a sigmoid saturation equation. The concentration which causes 50% enzyme inhibition (EC50) was then calculated from the dose response equation.
  • the final 10 uL kinase reaction consists of 0.6-76.0 ng FLT3 and 2 uM Tyr 02 peptide in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM Mg C12, 1 mM EGTA. After 1 hour kinase reaction incubation, 5 uL of a 1 :64 dilution of development reagent A was added.

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Abstract

L'invention concerne des composés représentés par la formule (I) et une méthode de traitement de patients souffrant de certains troubles inflammatoires, de troubles de démyélinisation, de troubles médiés par FLT3, de troubles médiés par CSF-1R, de cancers et de leucémies, consistant à administrer audit patient une quantité efficace d'un point de vue thérapeutique d'un composé représenté par la formule (I) ou d'un sel acceptable d'un point de vue pharmaceutique de celui-ci. L'invention concerne également des définitions des variables.
PCT/US2007/017300 2006-08-02 2007-08-02 Composés de n-oxyde et utilisations thérapeutiques WO2008016700A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279168A (zh) * 2016-08-12 2017-01-04 郑州大学 一种稠杂环6H‑苯并[b]咪唑[5,1,2‑de]喹嗪‑6‑酮类化合物、合成方法及用途

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Publication number Priority date Publication date Assignee Title
WO1992015583A1 (fr) * 1991-03-05 1992-09-17 British Technology Group Ltd. Imidazoacridines et leur utilisation en tant qu'antineoplasique

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WO1992015583A1 (fr) * 1991-03-05 1992-09-17 British Technology Group Ltd. Imidazoacridines et leur utilisation en tant qu'antineoplasique

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ZAFFARONI N ET AL: "Cell growth inhibition, G2M cell cycle arrest and apoptosis induced by the imidazoacridinone C1311 in human tumour cell lines" EUROPEAN JOURNAL OF CANCER, PERGAMON PRESS, OXFORD, GB, vol. 37, no. 15, October 2001 (2001-10), pages 1953-1962, XP004306001 ISSN: 0959-8049 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279168A (zh) * 2016-08-12 2017-01-04 郑州大学 一种稠杂环6H‑苯并[b]咪唑[5,1,2‑de]喹嗪‑6‑酮类化合物、合成方法及用途

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